The recovery of useful hand function after stroke is a major scientific challenge for stroke treatment today particularly for those with more severe paresis. In this population recovery mechanisms may differ from those with mild hemiparesis and may involve activation of the nonlesioned hemisphere. Therefore, for this population, therapies which can activate the nonlesioned cortex may play a critical role in inducing neural and functional recovery. Bilateral training is one such training approach. Current bilateral or unilateral approaches in isolation fail to lead to functional changes in arm and hand function in those with moderate severity stroke. We have developed an innovative sequential training approach in which subjects first perform bilateral proximal training and then participate in unilateral whole arm training assisted by the use of the Saeboflex orthosis. We propose that sequential training is critical for patients with moderate severity paresis. Our conceptual model is that bilateral training can induce nonlesioned hemispheric activity which creates a neural priming effect which then facilitates the recovery of hand function using unilateral whole arm training. To test our hypothesis that proximal bilateral training is a key element for promoting and priming the neural recovery, we propose to compare 6 weeks of proximal bilateral vs. proximal unilateral training on the same device followed by 6 weeks of the common unilateral whole arm training. Our aims include, 1) To determine the effects and durability of 12 weeks arm training with the combination of proximal bilateral and unilateral whole arm training (BU) compared to 12 weeks training with the combination of proximal unilateral followed by unilateral whole arm training (UU) on functional disability and 2) To assess the neural reorganization via patterns of activation in fMRI in those with moderate severity paresis for elbow and hand function after BU and UU training. Accomplishing these aims will determine the priming effect of bilateral proximal training given prior to a whole arm unilateral training and simultaneously the role of nonlesioned cortex activation in patients with moderate severity paresis. This will provide scientific evidence that can guide the use of bilateral and unilateral arm training interventions after stroke to achieve better functional outcomes that reduce disability in this underserved population. PUBLIC HEALTH RELEVANCE. This project is designed to test a new combination intervention for those with moderate severity arm paresis and to assess the underlying neural changes in the brain associated with the intervention. It combines sequentially, proximal bilateral arm training followed by whole arm training with just the paretic arm. Unilateral and bilateral interventions in isolation, for patients with this level of paresis, have not shown benefits to hand function. The potential benefit from this approach is that it may produce meaningful arm and hand functional gains in these patients who typically have not responded to treatments in isolation. It can also provide important information about brain changes seen with bilateral and unilateral training to guide the use of these interventions after stroke to achieve better functional results. [unreadable] [unreadable]